The instant invention relates to a polyglycerol derivative, to a medicament comprising such a polyglycerol derivative and to a method of manufacturing such a polyglycerol derivative.
As a part of the innate immune response to harmful stimuli such as physical injury, toxins, irritants or microbial infections, the acute inflammatory response triggers the removal of pathogens and subsequent dampening of inflammation is necessary to initiate the healing process. During this immune response increased leukocyte recruitment out of blood vessels into inflamed tissue is initiated which proceeds in a cascade-like fashion including the initial leukocyte tethering, subsequent rolling, firm adhesion to the endothelium, and subsequent transmigration into the subendothelial matrix.
The complex mechanism of leukocyte extravasation is mediated by cell adhesion molecules (CAMs) such as selectins and integrins, as well as chemokines and their respective ligands. For instance, the initial capture of leukocytes and subsequent rolling on the endothelium is initiated by the interaction of L-, P-, and E-selectin with their corresponding ligands consisting of fucosylated and sialylated glycoproteins.
Whereas acute inflammation describes a time limited and required process for healing, chronic inflammation is a persistent and unbalanced over reaction of the immune system, in which active inflammation and tissue damage, caused by prolonged excessive extravasation of leukocytes, are ongoing. Due to their essential role in leukocyte recruitment, different natural selectin inhibitors such as heparan sulfate, fucoidan and chondroitin sulfate have been investigated during the last decades for the treatment of inflammatory related diseases. However, the permanent suppression of the selectin-mediated immune response is certainly not the aim for a long term therapy, but is indeed useful for short-term treatments and diagnostic applications.
Another essential part within the inflammatory process is the activation of the complement system which can be achieved by the classical, alternative, and lectin pathway. Involving around 30 plasma proteins, the complement is responsible for opsonization of microorganisms for phagocytosis, recruitment of leukocytes and the lysis of pathogens.
Until today, heparin is the standard anticoagulant after surgery, but also provides high anti-inflammatory properties as found in an enzyme-linked immunosorbent assay (ELISA) investigating the binding affinity to L- and P-selectin and in an oxazolone induced allergic contact dermatitis mice model. Nevertheless, intravenous administration of heparin might lead to severe problems such as heparin-induced thrombocytopenia (HIT), prolonged bleeding, and the risk to acquire infections due to contaminated samples. These circumstances limit the usage of heparin as an anti-inflammatory compound.
Initially reported in 2004 by Turk et al. as a new synthetic heparin analog based on a dendritic polyglycerol (dPG) scaffold, dendritic polyglycerol sulfate (dPGS) was found to have an up to 24 times higher anti-inflammatory activity in vitro and only up to 34% anticoagulant activity compared to unfractionated heparin (UFH) [1]. Moreover, in a competitive, concentration dependent surface plasmon resonance (SPR)-based binding assay, a strong affinity of dPGS to L- and P-selectin was confirmed, with IC50 values up to the picomolar range, with respect to size and surface charge [2].
Screening of different dPG based anions, including phosphate, phosphonate, bisphosphonate, carboxylate, sulfonate, and sulfate, dPGS was identified as the most potent polyanion regarding L- and P-selectin binding [3]. The anti-inflammatory potential of dPGS was also demonstrated in vivo by a dose dependent reduction of ear swelling after administration in an acute allergic contact dermatitis model [4]. Effective shielding of leukocytes was also found in an experimental model of polymyositis, where reduced tissue destruction was observed [5]. Further, due to its high affinity to inflamed tissue, dPGS conjugates were successfully applied in the past as diagnostics in a collagen induced arthritis rat model, with cyanine near-IR dyes as the fluorescent read out [6].
Despite this enormous potential as a drug candidate, recent in vivo studies with radiolabeled dPGS, with a hydrodynamic diameter below 6 nm, revealed undesired biodistribution properties in mice [7]. Accumulation of dPGS in liver and spleen was observed even 21 days after intravenous administration. The unexpected biodistribution of dPGS is probably caused by ionic interactions of the polysulfate with serum proteins which might lead to the formation of aggregates and consequently to an increased hydrodynamic diameter, resulting in the recognition of the particles by the reticuloendothelial system (RES) [7, 8].
US 2011/0117009 A1 discloses a drug polymer conjugate comprising a pharmaceutically active compound and a dendritic polyglycerol. The conjugates are very complex molecules.
DE 10 2006 036 326 A1 discloses dendritic polyglycerol sulfates and dendritic polyglycerol sulfonates and their use for treating inflammatory diseases.